The incidence of new infections of HIV continues to rise, with the majority of these resulting from sexual transmission. In some areas of the world, the rate of increase indicates that HIV infection and its ultimate outcome--progression to AIDS--will continue to be a major health threat. Since changing human sexuality and behavior is an unrealistic goal, the most efficient way to decrease transmission is to prevent new infections by prophylactic vaccination. Thus, the long-term goal of this proposal is to develop an efficacious vaccine against HIV. Since the majority of new infections are acquired after exposure to secretions during sex or to blood while using contaminated needles for intravenous administration of drugs, a successful vaccine must elicit both systemic and mucosal immunity. The most direct way to test various antigens and antigen-delivery systems for optimum induction of an immune response and for protective efficacy is in an animal model. Since the only animal model that reproduces the natural history of HIV in humans, albeit without progression to AIDS, is HIV infection of chimpanzees, this model will be used (i) to develop reliable methods for infection by exposure of mucosal surfaces to HIV; (ii) to define mucosal and systemic humoral and cell- mediated immune responses induced by mucosal infection; and (iii) to use the resulting information to test the ability of HIV-specific immune responses elicited by candidate vaccines to prevent infection following mucosal or parenteral inoculation of HIV. Specifically, the proposed studies include the use of cell-free and cell-associated HIV to infect chimpanzees by exposure of the rectal mucosa or urethral canal to the virus. Reliable methods for these routes of transmission will complement an already established model of HIV infection of female chimpanzees via the cervical/vaginal mucosa. Mucosal and systemic humoral and cell- mediated HIV-specific immune responses induced as a result of infection by mucosal routes will be compared with responses that develop after intravenous inoculation. These results will form the basis on which to assess the potency of HIV immunogen(s) and their ability to elicit (putative) protective immune responses. Lastly, candidate HIV vaccines, modeled after vaccines that successfully prevent mucosal infections in the SIV-macaque model, will be tested in chimpanzees for immunogenicity, which will be evaluated relative to responses in HIV-infected chimpanzees, and for protective efficacy, to be tested in parallel by mucosal and parenteral exposure of immunized animals to infectious HIV. These studies should provide valuable information on the feasibility of developing vaccines that can induce both mucosal and systemic immune responses capable of preventing mucosal and parenteral infection by HIV.